Methods and compositions for the treatment of pain utilizing ropivacaine

ABSTRACT

Use of a pharmaceutically acceptable salt of ropivacaine for the manufacture of a pharmaceutical preparation with sensoric block and minimal motor blockade.

This application is a 371 of PCT/SE94/00469 filed May 26, 1994.

1. Field of the Invention

The present invention is related to the use of a low concentration of apharmaceutically acceptable salt of ropivacaine in the manufacture ofpharmaceutical preparations for pain relief post operatively and inlabour.

2. Background of the Invention

Post operative pain relief is still a problem within modern surgery.According to a newly published study about 70% of all patients treatedsurgically felt moderate to severe pain after the surgical treatment.

The need for qualified pain relief is greatest during the first 24 hoursafter the surgical treatment. The traditional method to treat thepatients is to give narcotics intramuscularly or intravenously. Suchtreatment is often insufficient as narcotic analgetics have manynegative effects. One disadvantage is depression of the breathing, whichmay occur even after treatment. This means that the patient must beintensively looked after by specialists.

A patient, who has been treated with morphine is tired, apathetic and isoften feeling sick. The patient thus has no interest in things aroundhim. It is thus difficult to take care of the patient and make himparticipate in respiratory exercises and prophylaxis for thromboses.

One method is administration epidurally, by infusion or intermittentinjections of local anaesthetics. Such treatments can only be carriedout on patients with epidural catheters being taken care of at anintensive care or post surgical unit by specially trained persons.

There has been a long felt need at ward level to be able to give agreater group of patients qualified pain relief by epidural infusion ofe.g. local anaesthetics instead of opiates.

Normally, with local anaesthetics a good blockade of the pain isobtained. The drawback is the motor blockade in the legs, which isdisturbing to the patients, who wants to give up the pain relieftreatment in advance. Among other effects the motor blockade means thatthe patient cannot leave his bed without assistance as the legs will notbear.

Outline of the invention

According to the present invention it has surprisingly been found thatthe local anaesthetic agent ropivacaine, described e.g. in WO/85/00599,in form of its hydrochloride can be given to the patient in a dosagewhich gives pain relief with minimal effect on motor function. This isat a dosage of lower than 0.5% by weight, especially from 0.01% to 0.45%by weight. Such low dosages are normally considered to be ineffective.The normal dosage is from 0.5-2% by weight.

The local anaesthetic compound used according to the invention is in theform of its pharmaceutically acceptable salts. It is especiallypreferred to use ropivacaine hydrochloride.

The local anaesthetic is incorporated into a solution.

The local anaesthetic composition contains less than 0.5% by weight ofthe local anaesthetic compound, preferably from 0.01 up to 0.45% byweight, especially preferred 0.1-0.3% by weight.

Pharmaceutical Preparations

EXAMPLES 1-3

Solution 5 mg/ml, 3 mg/ml, 2 mg/ml

    ______________________________________                                                       Examples                                                                      1      2             3                                         ______________________________________                                        Ropivacaine hydrochloride                                                                      0.53   kg    0.32 kg   0.21 kg                               monohydrate                                                                   Sodium hydroxide 2M to                                                        pH 5.0-6.0                                                                    Purified water qs ad                                                                           100    kg    100  kg   100  kg                               ______________________________________                                    

Ropivacaine is dissolved in the water. Sodium hydroxide is added to pH5.0-6.0. The resulting solution is autoclaved.

The best mode of carrying out the invention known at present is to usethe preparations according to Example 3.

Biological test

A double blind study of sensory and motor blockade with 0.1%, 0.2%, 0.3%ropivacaine and 0.25% bupivacaine during continuous epidural infusion inhealthy male volunteers.

Background

The aim of the study was to find a low concentration of ropivacainegiving a sufficient sensory block but as little or no motor block at allduring continuous epidural infusion. This study is a first step towardsfinding a low concentration of ropivacaine which later will be used fortreatment of post operative pain in patients. 37 volunteers participatedin the study. They were divided into 5 treatment groups, receivingeither 0.1%, 0.2% or 0.3% ropivacaine or 0.25% bupivacaine. There wasalso a control group receiving 0.9% saline. All solutions were firstgiven as a bolus dose of 10 ml, followed by a continuous epiduralinfusion at a rate of 10 ml/hour for 21 hours. During the infusion bothmotor and sensory blockade was tested using different methods. Thepostural stability of the volunteers was also evaluated.

Preliminary results

Group 1. No motor and sensory block was achieved in the volunteersreceiving saline.

Group 2. Bupivacaine 0.25% gave a good segmental spread (from the lowerpart of the abdomen to the lower part of the extremities) of sensoricblock during the infusion. All of the volunteers had a high degree ofmotor block and 75% (6/8) could not stand up at any occasion during theinfusion.

Group 3. Ropivacaine 0.3% gave an equal duration of sensory blockadecompared to bupivacaine 0.25%. The upper segmental spread of sensoricblock was somewhat higher than for bupivacaine. The lower segmentalspread of sensoric block was, after 10 hours of continuous infusion,shifted up to just below the knees compared to bupivacaine and at theend of infusion was found above the knees. The motorblock was somewhatless profound compared to bupivacaine. 5 out of 7 volunteers could notstand at any occasion during the infusion to perform the posturalstability tests.

Group 4. Ropivacaine 0.2% gave an equal sensory block compared tobupivacaine 0.25% in the lower part of the abdomen, but showed a lesssensory block around the ankles. After 10 hours of continuous infusionthe sensory block was less than for both ropivacaine 0.3% andbupivacaine. The motor block was less profound compared to the 0.3%ropivacaine as well as to the 0.25% bupivacaine solution. 25% (2/8) ofthe volunteers could not at any occasion stand up whereas the rest ofthe volunteers (6/8) could at some point during the infusion make someof the postural tests.

Group 5. Ropivacaine 0.1% gave, during the first 5 hours of theinfusion, a more narrow spread of the sensory block compared to the 0.2%ropivacaine solution. Normal sensation returned after 8 hours of theepidural infusion.

No serious or unexpected adverse events could be noted in any of thetest groups.

It was found that bupivacaine gives 75% higher motor blockade thanropivacaine, which only gives 25% at comparable dosage levels.

At the dosages 0.3% and 0.2% ropivacaine gives about the same motorblockade. At the dosage 0.1% it is less.

Conclusion

From the unique effect of ropivacaine the conclusion can be drawn thatsaid compound is especially useful for administering at low dosage topatients in the need of post surgical and labour pain treatment, withgood balance between sufficient sensoric block and a desirable minimaldegree of motor block.

I claim:
 1. A method for treating a human experiencing pain, said methodcomprising: administering to said human a composition comprising apharmaceutically acceptable salt of ropivacaine, wherein saidropivacaine is present in said composition at a concentration of lessthan 0.25% by weight.
 2. The method of claim 1, wherein said compositionis administered at a site permitting direct interaction between saidropivacaine and nerves in the spinal column of said human.
 3. The methodof claim 1, wherein said composition is administered epidurally.
 4. Themethod of any one of claims 1-3, wherein said pharmaceuticallyacceptable salt of ropivacaine is ropivacaine hydrochloride.
 5. Themethod of any one of claims 1-3, wherein said composition isadministered by continuous infusion.
 6. The method of claim 5, whereinsaid continuous infusion is at a flow rate of about 10 ml per hour. 7.The method of any one of claims 1-3, wherein said composition isadministered for post-surgical pain.
 8. The method of any one of claims1-3, wherein said composition is administered for labor pain.
 9. Apharmaceutical composition for use in acute pain management with minimalmotor blockade, comprising a pharmaceutically acceptable salt ofropivacaine at a concentration lower than 0.25% by weight.
 10. Thepharmaceutical composition of claim 9, wherein said pharmaceuticallyacceptable salt of ropivacaine is ropivacaine hydrochloride.